Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Nature. 2020 Oct;586(7831):807-811. doi: 10.1038/s41586-020-2668-z. Epub 2020 Aug 19.
The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias. Here we determine cryogenic electron microscopy structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with hepcidin and the iron mimetic cobalt. These structures and accompanying molecular dynamics simulations identify two metal-binding sites within the N and C domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy terminus of hepcidin directly contacts the divalent metal in the ferroportin C domain. Hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, in which only ferroportin molecules loaded with iron are targeted for degradation. More broadly, our structural and functional insights may enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.
人体内的铁血清水平受激素铁调素对铁输出转运蛋白 Ferroportin 的作用的严格控制。铁调素通过诱导 Ferroportin 的内化和降解来调节铁的吸收和再循环。异常的 Ferroportin 活性可导致铁过载疾病，如血色病，或铁限制性贫血。在这里，我们确定了铁调素和铁模拟物钴存在时，脂质纳米盘中 Ferroportin 的低温电子显微镜结构，包括apo 状态和复合物状态。这些结构和伴随的分子动力学模拟确定了 Ferroportin 的 N 和 C 结构域内的两个金属结合位点。铁调素以向外开放的构象结合 Ferroportin，并完全阻塞铁流出途径以抑制运输。铁调素的羧基末端直接与 Ferroportin C 结构域中的二价金属接触。铁调素与 Ferroportin 的结合与铁的结合偶联，铁的存在使铁调素的亲和力增加了 80 倍。这些结果表明了铁调素调节 Ferroportin 的模型，其中只有装载铁的 Ferroportin 分子被靶向降解。更广泛地说，我们的结构和功能见解可能使人们能够更有针对性地操纵铁动态平衡紊乱中铁调素- Ferroportin 轴。
